Enantioselective Stereodivergent Nucleophile‐Dependent Isothiourea‐Catalysed Domino Reactions

Abstract

Abstractα,β‐Unsaturated acyl ammoniums generated from the reaction of α,β‐unsaturated 2,4,6‐trichlorophenol (TCP) esters bearing a pendent enone with an isothiourea organocatalyst are versatile intermediates in a range of enantioselective nucleophile‐dependent domino processes to form complex products of diverse topology with excellent stereoselectivity. Use of either 1,3‐dicarbonyls, acyl benzothiazoles, or acyl benzimidazoles as nucleophiles allows three distinct, diastereodivergent domino reaction pathways to be accessed to form various fused polycyclic cores containing multiple contiguous stereocentres.

Synthesis of Heterocycles by isothiourea organocatalysis

“…With 1,3‐diketone the reaction proceeds via Michael‐addition‐Michael‐addition‐lactonization whereas with 2‐acyl benzothiazole and 2‐acyl benzimidazole, the process undergoes Michael‐Addition‐Lactamization‐Michael‐Addition (Scheme 53). [ 53 ] The high level of molecular complexity was attributed by nucleophile directed divergent domino reactions via formation of multiple bonds and contiguous stereocenters.…”

Evaluating aryl esters as bench-stable C(1)-ammonium enolate precursors in catalytic, enantioselective Michael addition–lactonisations

“…The aryl esters were then screened in our model reaction (Table 1, Entries 3-8). Electron deficient aryl esters (8)(9)(10)(11)(12) gave the desired dihydropyranone in significant yield (> 10%) (determined by NMR analysis of the crude material using 1,4-dinitrobenzene as an internal standard) while phenyl ester 13 gave no conversion. [19] Where significant yield was observed, dihydropyranone 2 was generally formed in good dr (> 84:16) and er (> 81:19) ( Table 1, Entries 3-7).…”

“…Notably, trichlorophenyl esters have also previously been found to be optimal for methods in α,β-unsaturated acyl ammonium catalysis, where the aryloxide is not required to operate as a nucleophile. [11,20] Further optimisation of the reaction with trichlorophenyl ester 12 was then investigated ( Table 2). [21] First, the reaction concentration was increased to 0.2 M resulting in a yield of 57% of 2 in 5 h at RT with no significant reduction in diastereo-or enantioselectivity (87:13 dr, 88:12 er) (Table 2, Entry 1).…”

“…Electron deficient aryl esters are effective acylating agents [9] and have been previously investigated as C(1)-ammonium and -azolium enolate precursors. [10] Within the field of isothiourea catalysis, aryl esters have been used for the formation of α,β-acyl ammonium intermediates [11] and have found particular utility in processes where the aryloxide leaving group is subsequently required to act as a nucleophile to facilitate catalyst turnover. [12] For example, 4-nitrophenyl esters have been used as substrates in stereoselective [2,3]sigmatropic rearrangements, [13,8b] as well as enantioselective additions to iminium ions [14] and in α,β-unsaturated acyl ammonium catalysis.…”

Tautomeric Equilibria in Solutions of 2-Phenacylbenzimidazoles

“…Light yellow solid; yield 1.22 g (87%); mp 182-183 ∘ C (lit. 176-178 [22], 179 [6], 178-178.5 [7], 178-179 ∘ C [4]); 1 H NMR (DMSO-d 6 from TMS) 4.68 (2H, s, CH 2 CO (K)), 6.10 (1H, s, CHO (O)), 7.17 (3H, m (O)), 7.42 (1H, m (O)), 7.45 7 (2H, m (O)), 7.49 (1H, m (K)), 7.57 (5H, m (K)), 7.68 (1H, m (K)), 7.86 (2H, m (O)), 8. 09 (2H, m (K)), 12.27 (1H, s, NH (O)), 12.34 (1H, s, NH (K)).…”